IL128993A - Method for producing ecteinascidin compounds 770 and 743 - Google Patents

Abstract

The present invention is directed to a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the present invention provides a synthetic route for the formation of ecteinascidin 743 (1), <IMAGE> an exceedingly potent and rare marine-derived antitumor agent which is slated for clinical trials. The process of this invention is enantio- and stereocontrolled, convergent and short. Also disclosed are novel process intermediates, useful not only in the total synthesis of ecteinascidin 743, but also other known ecteinascidin compounds, including derivatives and analogs thereof.

Description

128,993/2 A METHOD FOR PRODUCING ECTEINASCIDIN 770 and 743 743 -1770 p- t>N) n N tODf)!? ΓΙΥ) Υ> 128,993/3 SUMMARY OF THE INVENTION The present invention is directed to a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the present invention provides a synthetic route for the formation of ecteinascidin 743 (I), an exceedingly potent and rare marine-derived antitumor agent which is slated for clinical trials when adequate quantities become available.2'3 This process is enantio- and stereocontrolled, convergent and short. The preferred embodiment of the synthetic process of the present invention is best represented in the following Scheme I: , Scheme 1 13, Fl = ' 9-fluorenyl 2c , 1 , Ecteinascidin 743 128,993/3 As shown above in Scheme I, the preferred process for the synthetic formation of ecteinascidin 743 comprises the sequential steps of: (a) forming an a, ^-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate; (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, by selective allyl ester cleavage, Curtius rearrangement, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 into the compound of Formula 4 by catalytic hydrogenation over the rhodium catalyst, Knowles' catalyst Rh[(COD)R,R-DIPAMP]+ BF4" ; (d) converting the compound of Formula 4 into the compound of Formula 5 by acetal cleavage, wherein isolation and exposure of the resulting aldehyde to BF3.Et20 and 4 A mol sieves yields the bridged lactone compound of Formula 5; (e) converting the bridged lactone compound of Formula 5 to the free amino phenol compound of Formula 6 by hydrogenolysis over 10% Pd-C; (f) forming the protected c^arnino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl hydrogen malonate; (g) converting the protected ce-amino ester compound of Formula 7 to the chiral aldehyde 8 by reduction; (h) combining the compounds of Formulae 6 and 8 to afford the key monobridged pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulae 6 and 8 to give a coupled phenolic a-amino nitrile, followed by O-allylation 4 128,993/3 to give the allyl ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride; desilylating the lactol compound; and cyclizing the desilylated compound to afford the pentacycle compound of Formula 10 by an internal Mannich bisannulation; (i) converting the pentacycle compound of Formula 10 to the compound of Formula 11 by the selective trifluoromethane-sulfonation of the least hindered phenolic hydroxyl; followed by (1) selective silylation of the primary hydroxyl; (2) (2) protection of the remaining phenolic group as the methoxymethyl ether; (3) double deallylation; (4) reductive N-methylation; and (5) replacement of CF3 S03 by CH3 ; (j) Oxidizing the phenol compound of Formula 11 effected position-selective angular hydroxylation to give after desilylation the dihydroxy dienone compound of Formula 12; (k) forming the compound of Formula 13 by esterifying the primary hydroxyl function of the compound of Formula 12 with (S)-N-allyloxycarbonyl-S-(9-fluorenylmethyl) cysteine; (1) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by; (1) first reactmg the compound of Formula 13 with an in situ generated Swern reagent; (2) followed by the formation of the exendo quinone methide, (3) destruction of the excess Swern reagent; (4) addition of excess N-tert-butyl-N',N"- tetramemylguanidine to generate the 10-membered lactone bridge; and (5) addition of excess Ac20 to acetylate the 128,993/4 resulting phenoxide group; (m) cleaving the N-allyloxycarbonyl group of the compound of formula 14 6 128,993/5 oxidizing the resulting a-amino lactone to the corresponding a-keto lactone by transamination thereby forming the compound of Formula 15; 7 (n) stereospecifically forming spiro tetrahydro-isoquinoline compound by reacting the compound of Formula 15 with 2-[3 -hydroxy ~4-methoxy-phenyljethylamine; 8 128,993/5 (o) followed by methoxymethyl cleavage (yielding Et 770) followed by the replacement of CN by HO, with reference to the methods of Example 38, to form the compound of formula 1, ecteinascidin 743. 8a 128,993/3 In addition to the preferred process of Scheme I, the present invention also provides a novel intermediate compourid of formula II useful for the synthesis of known ecteinascidin compounds, as well as analogs and derivatives of said compounds.. 128,993/3 mol sieves in CH2 Cl2 at 23 °C for 18 h gave the bridged lactone 5 in 73% yield.7 Hydrogenolysis of 5 (1 atm H2, 10% Pd-C, EtOAc, 23 °C, 6 h) produced the free amino phenol 6 in 100% yield. The protected a-arnino ester 7 was synthesized by an analogous route, starting with 3,5-bis-½rt-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl hydrogen malonate, and then reduced (2 equiv of diisobutylaluminum hydride in CH2 Cl2 at -78 °C or 1 h) to give the chiral aldehyde 8 (>90% yield).

The next stage of the synthesis, which involved the combination of the building blocks 6 and 8 and subsequent elaboration to construct the key monobridged pentacyclic intermediate 10, commenced with the reaction of 6 and 8 in HO Ac containing 25 equiv of KCN at 23 °C for 18 h to give a coupled phenolic a-amino nitrile (61%) and subsequent O-allylation to give allyl ether 9 in 87% yield (2 equiv of Cs2 C03 and 5 equiv allyl bromide in DMF at 23 °C for 1 h). Starting with intermediate 10, it is believed that all known ecteinasicin compounds can be synthetically prepared, as well as analogs and derivatives thereof.

Treatment of 9 with 1.2 equiv of diisobutylaliirninum hydride in toluene at -78 °C for 5 h effected the selective conversion of the lactone function to a lactol which was desilylated by exposure to excess KF.2H20 in CH3OH at 23 °C for 20 min and cyclized to pentacycle 10 by internal Mannich bisannulation with 20 equiv of CH3SO3H in C¾ Cl2 in the presence of 3 A mol sieves at 23 °C for 5 h (55% overall from 9).

Selective trifluoromethane-sulfonation of the least hindered phenolic hydroxyl (5 equiv of Tf2 Ph, Et3 N, 4,4-dimethylaminopyridine (DMAP) in CH2C12 at 23 °C for 6 h; 72% yield) was followed by (1) selective silylation of 128,993/3 the primary hydroxyl (excess tert-butyldiphenylsilyl chloride-DMAP in CH2 Cl2 at 23 °C for 13 h; 89%), (2) protection of the remaining phenolic group as the methoxymethyl ether (MeOC¾Br and i-Pr2NEt in CH2 Cl2 at 23 °C for 20 min; 92%), (3) double deallylation (Bu3SnH, cat. Cl2Pd(Ph3)2, excess HOAc in CH2 Cl2 at 23 °C for 15 rnin; 100%), (4) reductive N-methylation (excess formalin, NaBH3CN, HOAc in CH3CN at 23 °C for 30 min; 95%), and (5) replacement of CF3S03 by CH3 (excess Me4Sn, Cl2Pd(Ph3P)2, LiCl, DMF, 80 °C, 2 h) to give 11 in 83% yield.

Oxidation of the phenol 11 with 1.1 equiv of (PhSeO)2O in CH2C12 at 23 °C for 15 min effected position-selective angular hydroxylation to give after desilylation (2 equiv of B114NF in THF at 23 °C for 10 min) the dihydroxy dienone 12 (75% from 11).

The last three rings of ecteinascidin 743, the 10-membered lactone bridge and the spiro tetrahydro-isoquinoline subunit, were then added in the final stage of the synthesis of 1 by the following sequence of reactions: The primary hydroxyl function of 12 was esterified with (S)-N-allyl-oxycarbonyl-S-(9-fluorenylmethyl) cysteine using 5 equiv of l-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide-HCl and 5 equiv of DMAP in CH2C12 at 23 °C for 30 min to form 13 (91%) which was then transformed in one flask to the bridged lactone in 79% overall yield by the operations: (1) reaction of 13 with the in situ generated Swern reagent from excess triflic anhydride and DMSO at -40 °C for 30 rnin,8a (2) addition of z'-Pr2 Et and warming to 0 °C for 30 min to form the exendo quinone methide,8 (3) quenching with tert-butyl alcohol (to destroy excess Swern reagent), (4) addition of excess N-tert-bvAyl-N',N"- tetramethylguanidine9 to convert the 9-fluorenylmethyl thiolether to the thiolate ion and to promote nucleophilic addition of sulfur to the quinone methide to 128,993/3 generate the 10-membered lactone bridge, and (5) addition of excess Ac2 O to acetylate the resulting phenoxide group. The N-allyloxycarbonyl group of 14 was cleaved (excess Bu3SnH, HOAc and cat. Cl2 Pd(PPh3)2 in CH2 Cl2 at 23 °C for 5 min; 84%) and the resulting a-amino lactone was oxidized to the corresponding a-keto lactone by transamination with the methiodide of pyridine-4-carboxaldehyde, DBU, and DMF in CH2C12 at 23 °C for 40 min to give 15 (70%). Reaction of 15 with 2-3-hydroxy-4-methoxy-phenylethylamine (16) in EtOH in the presence of silica gel at 23 °C generated the spiro tetrahydro-isoquinoline stereospecifically (82%) which was then subjected to methoxymethyl cleavage (4:1:1 CF3C02 H-H20-THF at 23 °C for 9 h) and replacement of CN by HO (AgNC-3 in CH3CN-H20 at 23 °C for 11 h) to form in high yield ecteinascidin 743 (1), identical in all respects with an authentic sample.10 The synthetic process of the present invention provides access not only to 1 but also to a host of other members of the ecteinascidin family and analogs, as well as to related simpler structures such as the saframycins.11 The preparation and characterization of the novel intermediates described above are described in detail below in the Examples.

The present invention will be further illustrated with reference to the following examples which aid in the understanding of the present invention, but which are not to be construed as limitations thereof.

EXAMPLES General Procedures. All reactions were performed in flame-dried round bottom or modified Schlenk (Kjeldahl shape) flasks fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. 13 128,993/3 Where necessary (so noted), solutions were deoxygenated by alternate evacuation/argon flush cycles (greater than three iterations). Organic solutions were concentrated by rotary evaporation below 30 °C at ca. 25 Torr. Flash column chromatography was performed as described by Still et al. employing 230-400 mesh silica gel.12 Thin-layer chromatography (analytical and preparative) was performed using glass plates pre-coated to a depth of 0.25 mm with 230-400 mesh silica gel impregnated with a fluorescent indicator (254 ran).

Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran and ethyl ether were distilled from sodium benzophenone ketyl. Dichloromethane, hexanes, N,N-diisopropyl-ethylamine, diisopropylarnine, triemylamine, pyridine, toluene, benzene, TMEDA, pipendine, and acetonitrile were distilled from calcium hydride at 760 Torr. The molarity of n-butyllithium solutions was determined by titration using diphenylacetic acid as an indicator (average of three determinations).13 Instrumentation. Infrared (IR) spectra were obtained using a Nicolet 5ZDX FT-IR spectrophotometer referenced to a polystyrene standard. Data are presented as follows: frequency of absorption (cm"1), and intensity of absorption (s=strong, m=medium, w=weak). Proton and carbon-13 nuclear magnetic resonance (1H MR or 13C NMR) spectra were recorded with a Bruker AM500 (500 MHz), a Bruker AM400 (400 MHz), or a Bruker AM300 (300 MHz) NMR spectrometer; chemical shifts are expressed in parts per million (d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHC13 : d 7.26, CeHDs : d 7.20, CDHC12: d 5.38, CD3COCD2H: d 2.04, CD2HOD: d 3.30). Data are presented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=quartet, m=multiplet and/or multiple resonances), integration, coupling constant in Hertz (Hz), and assignment. Chiral high performance liquid chromatography (HPLC) was 14 128,993/3 conducted with an Isco 2350 equipped with the specified column (see below).

Melting points were recorded with a Fisher- Johns melting point apparatus and are uncorrected.

The following schemes 2-7, illustrate the examples which follow: Scheme 2 - Left Side Fragment of the reaction scheme 17 18 Hxs= hexanes TMEDA = tetramethylethylene- diamine 22 BnBr=benzylbromide 128,993/4 24 BOPC!(L5 equiv), LDA * lithiumdiisopropylaniide Et3N(5.0 equiv), B0PC1 = bis (2-oxo-3-oxazalidinyl)phosphinic chloride CH2Cl2, 23°C, 1.5 h; 73% Scheme 3 - Left Fragment II Piperidine(2.0 equiv), AcOH(4.0 PhH, 4A molec. sieves, 23 *C, 20b; 99% 16 128,993/3 Scheme 4 - Right Side Fragment of the Reaction Scheme Dibal=diisobutylaluminium 34 16a 128,993/1 41 18 128,993/3 Scheme 6 - JPentacycle II Bii3SnH(5 equiv), (PPh3)2PdCl2, AcOH (20 equiv), CH2C1223°C, min; quant 4 18a , 128,993/1 , Example 1 - Methoxymethyl Ether 18: Methoxymethyl Ether 18: To a solution of 17 (10.2 g, 74.3 mmol, 1 equiv) in a mixture of ethyl ether and DMF (4:1 (v/v), 100 mL) at 0 °C was added a suspension of sodium hydride in mineral oil (57% (w/w), 4.07 g, 96.6 mmol, 1.3 equiv). The resulting suspension was stirred at 0 °C for 35 min, and then bromomethylmethyl ether (7.89 mL, 96.6 mmol, 1.3 equiv) was added dropwise. The suspension was stirred at 0 °C for 5 min and then at 23 °C for 1 h before the excess sodium hydride was neutralized with the slow addition of methyl alcohol (5 mL) at 0 °C. The solution was partitioned between ethyl acetate (500 mL) and water (300 mL), and the organic phase was then washed with saturated aqueous sodium chloride solution (200 mL), dried (sodium sulfate), and concentrated. The residue was purified by flash column chromatography (7% ethyl acetate in hexanes) to afford 18 (13.1 g, 90%) as a colorless oil. Rf 0.32 (10% ethyl acetate in hexanes); 1H NMR (500 MHz, CDC13) δ 6.70 (d, 1H, J = 8.4 Hz, ArH), 6.62 (d, 1H, J = 2.4 Hz, ArH), 6.49 (dd, 1H, J = 8.4, 2.4 Hz, ArH), 5.91 (s, 2H, ArOCH2 OAr), 5.10 (s, 2H, MOM CH2), 3.50 (s, 3H, OCH3); 13C NMR (100 MHz, CDC13) δ 152.5, 148.1, 142.5, 108.5, 108.0, 101.1, 99.7, 95.5, 60.3, 55.8, 14.1; IR (neat film) 2990 (m), 2847 (m), 2827 (m), 1632 (m), 1611 (m), 1502 (s), 1486 (s), 1451 (m), 1245 (s), 1213 (s), 1 152 (s), 1069 (s), 1004 (s), 922 (s) cm"1; HRMS (E ) m/z: calcd for C9H10O4 (M+) 182.0578, found 182.0582. 21 128,993/3 Example 2 - Methoxymethyl Ether 19: To a solution of 18 (6.76 g, 37.1 mmol, 1 equiv) and tetramethylethylenediamine (16.8 mL, 111 mmol, 3.0 equiv) in hexanes (70 mL) at 0 °C was added dropwise a solution of n-butyllithium (1.55M in hexanes, 72.0 mL, 74.2 mmol, 2.0 equiv), and the resulting yellow suspension was stirred at 0 °C for 2.5 h. A solution of iodomethane (11.5 mL, 186 mmol, 5.0 equiv) in diethyl ether (12 mL) was added dropwise at 0 °, and the resulting slurry was stirred at 23 °C for 1 h before it was quenched with the slow addition of water (10 mL). The reaction mixture was diluted with diethyl ether (500 mL), the product solution was washed sequentially with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), and then was dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution: 2% → 3% ethyl acetate in hexanes) to afford 19 (6.32 g, 87%) as a pale yellow oil. Rf 0.31 (10% ethyl acetate in hexanes); 1H NMR (500 MHz, CDC13) δ 6.57 (d, 1H, J = 8.5 Hz, ArH), 6.51 ( , To a solution of 19 (7.50 g 38.3 mmol, 1 equiv) in a 1 :1 (v/v) mixture of diethyl ether and hexanes (70 mL) at 0 °C. was added dropwise a solution of n-butyllithium ( 1.50M in hexanes, 77.0 mL, 115 mmol, 3.0 equiv). The reaction mixture was allowed to warm to 23 °C and was stirred at this temperature for 5 h. The yellow suspension was cooled to -10 °C, and N,N-dimethylformamide (14.7 mL, 191 mmol, 5.0 equiv) then was added. The resulting solution was stirred at -10 °C for 1 h. Excess base was neutralized by the slow addition of glacial acetic acid (10 mL) at -10 °C, and the resulting suspension was stirred at 23 °C for 5 min. The reaction mixture was diluted with ethyl acetate (500 mL), and the product solution was washed sequentially with saturated aqueous sodium bicarbonate solution (400 mL), water (400 mL), and saturated sodium chloride solution (300 mL). The organic phase was dried (sodium sulfate) and concentrated, and the product 20 was crystallized from 10% ethyl acetate in hexanes (4.05 g). The mother liquor was purified by flash column chromatography (15% ethyl acetate in hexanes) to afford additional 20 (1.35 g) (64% total) as a pale yellow solid (mp 91.5 °C). Rf 0.22 (ethyl acetate in hexanes); 1H NMR (400 MHz, CDC13) δ 10.15 (s 1H, CHO), 7.13 (s, 1H, ArH), 6.03 (s, 2H, ArOCHzOAr), 5.03 (s, 2H, MOM C¾), 3.59 (s, 3H, OCH3), 2.19 (s, 3H, ArCH3); 13C NMR (100 MHz, CDC13) δ 189.0, 157.0, 152.4, 144.2, 123.8, 113.7, 103.3, 102.1, 101.3, 58.0, 9.4; ffi. (neat film) 2925 (w), 1670 (s), 1614 (w), 1473 (m), 1452 (m), 1399 (m), 1280 (m), 1155 (m), 1059 (m), 935 (s), 927 (s), 860 (m) cm'1 ; HRMS (Ef) mJr. calcd for CnHnOsiM*) 224.0684, -found 224.0684.

, Example 4 - Aldehyde 22: 21 To a solution of 20 (3.70 g, 16.5 mmol, 1 equiv) in dichloromethane (50 mL) and water (1.0 mL) at 0 °C was added methanesulfonic acid (1.50 mL, 22.5 mmol, 1.4 equiv). The reaction mixture was then neutralized with saturated aqueous sodium bicarbonate solution (50 mL) at 0 °C, and the resulting mixture was partitioned between saturated aqueous sodium bicarbonate solution (400 mL) and dichloromethane (3 ·* 200 mL). The combined organic layers were dried (sodium sulfate) and concentrated to afford 21 as a crude intermediate. To a solution of 21 in N,N-amiethylformamide (16.0 mL) at 0 °C was added a suspension of sodium hydride in mineral oil (57% (w/w), 903 mg, 21.5 mmol, 1.3 equiv), and the resulting suspension was stirred at 0 °C for 40 min. Benzyl bromide (2.94 mL, 24.8 mmol, 1.5 equiv) was added to the reaction mixture at 0 °C, and the resulting suspension was stirred at 23 °C for 30 rnin. Excess base was neutralized by the slow addition of methanol (2.0 mL) at 0 °C, and the reaction mixture was diluted with ethyl acetate (250 mL). The product solution ~was washed sequentially with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), then was dried (sodium sulfate) and concentrated. 128,993/1 23a The residue was purified by flash column chromatography (10% ethyl acetate in hexanes) to afford 22 (3.85 g, 86%) as a viscous syrup. Rf 0.18 (10% ethyl acetate in hexanes); Ή NMR (400 MHz, CDC13) δ 10.08 (s, 1H, CHO), 7.40 (m, 5H, Bn ArH), 7.12 (s, 1H, ArH), 6.04 (s, 2H, ArOCH2OAr), 4.93 (s, 2H, Bn CH2), 1.60 (s, 3H, ArCH3); 13C NMR (100 MHz, CDC13) δ 188.5, 158.3, 152.6, 144.1, 135.7, 128.7, 128.3, 123.6, 113.8, 103.2, 102.1, 78.5, 11.8, 9.1; IR (neat film) 2923 (w), 1674 (s), 1612 (w), 1470 (m), 1420 (m), 1375 (m), 1352 (m), 1278 (s), 1170 (m), 1096 (s), 1069 (m) cm*1 ; HRMS (EI*) m/z: calcd 24 128,993/3 for Ci6Hi404(M+) 270.0892, found 270.0892.

Example 5 - Monoallylmalonate 24: LDA(1.0 equiv), Et20, 23 24 A solution of n-butyllithium (1.56M in hexanes, 19.2 mL, 30.0 mmol, 1.0 equiv) was added to a solution of ftisopropylamine (5.47 mL, 39.0 mmol, 1.3 equiv) in ethyl ether (30.0 mL) at -78 °C. The reaction flask was transferred briefly to an ice bath (10 inin), and then was recooled to -78 °C. Allyl acetate 23 (3.23 mL, 30.0 mmol, 1 equiv) was added to the cold solution of lithium diisopropylamide, and the resulting solution was stirred at -40 °C for 1 h. The reaction mixture was cooled to -78 °C and excess solid carbon dioxide was added to the reaction mixture before it was allowed to warm to 23 °C over a 1 h period. The turbid solution was diluted with water (100 mL) and was washed with ethyl ether (3 x 50 mL). The aqueous layer was acidified at 0 °C to pH=2 with the slow addition of concentrated hydrochloric acid and then was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated to afford crude acid 24 (3.35 g, 76%) as a pale yellow oil, which was used without further purification. 1H NMR (400 MHz, CDC13) δ 5.92 (m, 1H, CH2-CH-), 5.36 (m, 1H, C¾=CH-), 5.27 (m, 1H, CH2-CII-), 4/.S (dt, 2H, J = 5.7, ~ 1 Hz, CH2=CHCH2-), 3.48 (s, 2H, CH2); TR (neat film) 3300-2400 (m), 1744 (s), 1322 (m), 1156 (m) cm 1. , 3 Example 6 - AIIyI-2,2-dimethoxyethyI Malonate 26: 26 To a solution of acid 24 (7.50 g, 52.0 mrnol, 1 equiv), 2,2-dimethoxyethanol (25) (5.50 g, 52.0 mrnol, 1.0 equiv), and triethylamine (36.0, 258 mmol, 5.0 equiv) in dichoromethane (100 mL) was added solid BOP-C1 [bis(2-oxo-3-oxazolidinyl)phosphinic chloride ] (20.0 mg, 78.7 mmol, 1.5 equiv), and the resulting slurry was stirred at 23 °C for 1 h. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (400 mL), and the product solution was washed sequentially with water (2 x 300 mL) and saturated aqueous sodium chloride solution (300 mL). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 20-33% ethyl acetate in hexanes) to afford 26 (8.81 g, 73%) as a colorless liquid. Rf 0.26 (25% ethyl acetate in hexanes); 1H NMR (300 MHz, CDC13) δ 5.91 (m, 1H, CH2=CH-), 5.34 (m, 1H, CH2=CH-), 5.26 (m, 1H, CH2=CH), 4.64 (dt, 2H, J = 5.6, ~ 1 Hz, CH2=CHCH2), 4.58 (t, 1H, J = 5.3 Hz, CH(OCH3)2), 4.17 (d, 2H, J = 5.3 Hz, CH2 CH(OCH3)2), 3.46 (s, 2H, CHz), 3.39 (s, 6H, OCH3); 13C NMR (100 MHz, CDC13) δ 166.0, 165.9, 131.5, 118.7, 101.0, 66.0, 63.8, 53.9, 41.2; FTIR (neat film) 2955 (m), 1757 (s), 1738 (s), 1447 (m), 1412 (m), 1367 (s), 134Ό (s), 1323 (s), 1276 (s), 1193 (s), 1134 (s), 1102 (s), 1078 (s), 1046 (s) cm-1 ; HRMS (CI4) m/r. Calcd for CioH2oN06(M+ H4)+ 250.1291, found 250.1296.

, Example 7 - ,β -Unsaturated Diester 2: 2 To a mixture of aldehyde 20 (3.84 g, 14.2 mmol, 1.1 equiv), 26 (3.00 g, 12.9 mmol, 1 equiv), piperidine (2.80 mL, 28.4 mmol, 2.0 equiv), and crushed activated 4 A molecular sieves (~ 6 g) in benzene (40 mL) was added dropwise glacial acetic acid (3.25 mL, 56.8 mmol, 4.0 equiv), and the resulting suspension was stirred at 23 °C for 18 h. The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (gradient elution: 20 → 33% ethyl acetate in hexanes) to afford 2 (6.20 g, 99%) as an inseparable mixture of E/Z isomers (1.3:1). Rf 0.62 (10% ethyl ether in dichloromethane); 1H NMR (500 MHz, CDC13) δ major isomer: 8.07 (s, 1H, ArCH), 7.38 (m, 5H, Ph-H), 6.83 (s, 1H, ArH), 5.98 (s, 2H, ArOCH2OAr), 5.75 (m, 1H, CH2=CH), 5.34 (m, 1H, CH2=CH), 5.24 (m, 1H, CH2=CH), 4.77 (s, 2H, Bn C¾), 4.72 (m, 2H, CH2=CHCH2), 4.64 (t, 1H, J = 5.6 Hz, CH(OCH3)2), 4.32 (d, 2H, J = 5.6 Hz, CH2CH(OCH3)2), 3.41 (s, 6H, OCH3), 128,993/1 26a 2.16 (s, 3H, ArCH3), minor isomer: 8.06 (s, 1H, ArCH), 7.38 (m, 5H, Ph-H), 6.76 (s, 1H, ArH), 5.98 (s, 2H, ArOCH2OAr), 5.73 (m, 1H, CH2=CH), 5.38 (m, 1H, CH2=CH), 5.28 (m, 1H, CH2=CH), 4.77 (s, 2H, Bn CH2), 4.78 (m, 2H, CH2=CHCH2), 4.59 (t, 1H, J = 5.6 Hz, CH(OC¾)2), 4.23 (d, 2H, J = .6 Hz, CH2CH(OCH3)2), 3.40 (s, 6H, OCH3), 2.16 (s, 3H, ArC¾); 13 C MR (100 MHz, CDC13) 5 166.3, 166.2, 163.9, 163.8, 153.5, 149.5, 143.6, 139.1, 139.0, 136.3, 131.8, 131.4, 128.6, 128.4, 123.6, 119.4, 119.1,118.2, 114.1, 104.7, 104.6, 101.7, 101.2, 101.0, 77.5, 77.4, 66.2, 65.8, 63.9, 63.8, 53.9, 53.8, 14.1, 9.3; IR (neat film) 2928 (w), 1732 (s), 1609 (m), 1476 (m), 1423 (m), 1243 (s), 1217 (s), 1186 (s), 1096 (s), 1079 (s) cm'1 ; HRMS (FAB*) m/z: 128,993/3 calcd for C26H28O9 Na (MNa*) 507.1631, found 507.1640.

Example 8 -α, β Unsaturated Acid 27: 27 To solution of 2 (6.20 g, 12.8 mmol, 1 equiv) in tetrahydrofuran (30 mL) was added sequentially a solution of Iriethylarnmonium formate (I in tetrahydrofuran, 38.4 mL, 38.4 mmol, 3.0 equiv) and solid tetrakis-(triphenyl- phosphine)palladium (120 mg), and the resulting solution was stirred at 23 °C for 4 h. All volatiles were removed in vacuo, and the residue was purified by flash column chromatography (10% methyl alcohol in dichloromethane) to yield the yellow oil 27 (5.33 g 94%) as a mixture of E/Z isomers (4:1). Rf 0.21 (10% methyl alcohol in dichloromethane); 1H NMR (500 MHz, CDC13) δ major isomer: 8.19 (s, 1H, ArCH), 7.40 (m, 5H, Ph-H), 6.82 (s, 1H, ArH), 6.00 (s, 2H, ArOCH2OAr), 4.78 (s, 2H, Bn CH2), 4.61 (t, 1H, J = 5.8 Hz, CH(OCH3)2), 4.29 (d, 2H, J=5.8 Hz, C02 CH2), 3.40 (s, 6H, OCH3), 2.15 (s, 3H, ArCH3), minor isomer: 8.21 (s, 1H, ArCH), 7.40 (m, 5H, Ph-H), 7.13 (s, 1H, ArH), 5.96 (s, 2H, ArOCH2OAr), 4.78 (s, 2H, Bn CH2), 4.59 (t, 1H, J = .8 Hz, CH(OCH3)2), 4.24 (d, 2H, J = 5.8 Hz, C02CH2), 3.38 (s, 6H, OCH3), 2.15 (s, 3H, ArCH3); 13C NMR (100 MHz, CDC13) δ 169.3, 168.9, 166.3, 164.8, 153.8, 149.9, 143.6, 143.5, 141.6, 141.4, 136.1, 135.9, 128.7, 128.5, 128.4, 128.3, 122.0, 121.5, 119.2, 119.1, 114.0, 113.8, 105.2, 104.7, 101.7, 101.0, 100.9, 77.6, 77.5, 63.9, 63.7, 53.9, 53.8, 53.3, 50.3, 9.2; JR (neat film) 3500-2500 (m), 2958 (m), 1735 (s), 1701 (s), 1608 (m), 1476 (s), 1423 (s), 1258 (s), 1218 (m), 1188 (s), 1135 (m), 1096 (s) cm"1 ; MS (EI+) m/z: 444 (M+).

, Example 9 - Benzyl Carbamate 3: 3 To a mixture of 27 (5.32 g, 11.2 mmol, 1 equiv), triemylamine (6.24 mL, 44.8 mmol, 4.0 equiv), and crushed, activated 4 A molecular sieves (~ 20 g) in toluene (53 mL) was added diphenylphosphoryl azide (3.10 mL, 14.4 mmol, 1.2 equiv), and the resulting suspension was heated to 70 °C for 2 h. The reaction mixture was cooled to 23 °C, and benzyl alcohol (1.73 mL, 16.8 mmol, 1.5 equiv) was then added. The suspension was stirred at 23 °C for 1 h, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (gradient elution: 20 → 50% ethyl acetate in hexanes) to afford 3 (5.90 g, 93%) as a pale yellow solid (mp 102-103°C). Rf 0.25 (33% ethyl acetate in hexanes); 1H NMR (400 MHz, CDC13) δ 7.40 (m, 1H, Ph-H & ArCH), 6.92 (s, 1H, ArH), 6.70 (s (br), 1H, NH), 5.99 (s, 2H, ArOCH2OAr), 5.10 (s, 2H, Cbz CH2), 4.70 (m (br), 2H, Bn CH2), 4.58 (t (br), 1H, J = unres, CH(OCH3)2), 4.23 (d (br), 2H, J = unres, C02CH2CH), 3.39 (s, 6H, OCH3), 2.18 (s, 3H, ArCH3), Z configuration verified by 5.8% NOE of Ar-H upon irradiation of N-H; 13C NMR (100 MHz, CDC13) δ 165.0, 151.7, 148.1, 143.4, 136.3, 135.9, 128.6, 128.5, 128.4, 128.3, 128.1, 126.3, 123.6, 120.1, 113.9, 105.0, 101.5, 101.1, 67.3, 64.0, 53.9, 9.4; IR (neat film) 3350 (w, br), 2940 (w), 1718 (s), 1498 (m), 1473 (m), 1423 (m), 1247 (s), 1193 (s), 1130 (m), 1094 (s) H)69 (m) cm"1 ; HRMS (FAB*) mJr. calcd for C3oH3iN09Na (MNa*) 572.1896, found 572.1909. 29 128,993/3 Example 10 - Protected Amino Acid 4: Rh[(COD)R,R-DiPAMP]+BF4' (20 mg) in a mixture of methyl alcohol and dichloromethane (10:1 (v/v), 11.0 mL) was placed in a high pressure Parr reactor and was purged with hydrogen gas (5 x 50 psi). The reaction mixture was sealed under hydrogen (50 psi) and was stirred at 23 °C for 16 h. The solution was concentrated, and the residue was purified by flash column chromatography (gradient elution: 33 → 50% ethyl acetate in hexanes) to yield 4 (774 mg, 97%) as a white solid (mp 93.5 - 94.0 °C). Rf 0.25 (33% ethyl acetate in hexanes); ee: 96% (HPLC Chiracel OD, 10% isopropyl alcohol in hexanes); [a]D23 =1.9 0 (c = 0.67, CH2C12); 1H NMR (500 MHz, CDC13) δ 7.36 (m, 10H, Ph-H), 6.50 (s, 1H, ArH), 5.92 (s, 2H, ArOCH2OAr), 5.75 (d, 1H, J = 7.8 Hz, NH), 5.03 (s, 2H, Cbz CH2), 4.76 (s, 2H, Bn CH2), 4.53 (m, 1H, CHC02), 4.46 (t, 1H, J = .6 Hz, CH(OCH3)2), 4.09 (m, 2H, C02CH2CH), 3.35 (s, 6H, OCH3), 3.06 (dd, 1H, J = 4.7, 13.4 Hz, ArCH2), 2.94 (dd, 1H, J = 7.6, 13.4 Hz, ArCH2), 2.20 (s, 3H, ArCH3); 13C NMR (126 MHz, CDC13) δ 171.3, 155.8, 150.5, 146.2, 143.3, 136.8, 136.5, 128.5, 128.4, 128.1, 127.9, 127.8, 121.2, 113.6, 107.1, 101.2, 101.1, 75.4, 66.6, 63.6, 55.2, 53.9, 53.8, 32.7, 9.7; JR (neat film) 3390 (w), 2949 (w), 1724 (s), 1500 (m), 1476 (s), 1213 (m), 1034 (m), 1091 (s), 1027 (m) cm-1 ; HRMS (EI4) mfz: Calcd for 551.2153, found 551.2159.

, To a solution of 4 (175 mg, 0.318 mmol, 1 equiv) and water (57 mL, 3.18 mmol, 10.0 equiv) in dichloromethane (10.0 mL) at 0 °C was added boron trifiuoride etherate (392 mL, 3.18 mmol, 10.0 equiv), and the resulting solution was stirred at this temperature for 10 min. The Lewis acid was neutralized with the slow addition of saturated aqueous sodium bicarbonate solution (10.0 mL), and the resulting mixture was then partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and dichloromethane (40 mL). The aqueous phase was extracted further with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (sodium sulfate) and concentrated to afford crude aldehyde 28 of sufficient purity. Rf 0.24 (50% ethyl acetate in hexanes); 1H NMR (500 MHz, CDC13) δ 9.44 (s, 1H, CHO), 7.32 (m, 10H, Ph-H), 6.50 (s, 1H, ArH), 5.95 (s, 2H, ArOCH2OAr), 5.72 (d, 1H, J = 7.4 Hz, NH), 5.07 (d, 1H, J = 10.7 Hz, Cbz CH2), 5.02 (d, 1H, J = 10.7 Hz, Cbz CH2), 4.78 (d, 1H, J = 10.2 Bn CH2), 4.74 (d, 1H, J = 10.2 Bn CH2), 4.58 (m, 1H, CHC02), 4.53 (d, 1H, J = 16.8 Hz, CH2CHO), 4.48 (d, 1H, J = 16.8 Hz, CH2CHO), 3.04 (m, 2H, ArCH2), 2.20 (s, 3H, ArCH3); IR (neat film) 3353 (w, br), 2913 (w), 1724 (s), 1476 (m), 1254 (m), 1215 (m), 1184 (m), 1090 (s), 1063 (m), 1027 (m) cm"1. 31 128,993/3 Borontrifluoride etherate (640 mL, 5.20 mmol, 16.4 equiv) was added to a mixture of crude aldehyde 28 (0.318 mmol, 1 equiv) and crushed, activated 4 A molecular sieves (2.8 g) in dichloromethane (32 mL) at 0 °C, and the resulting suspension was stirred at 23 °C for 18 h. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution (100 mL), and the mixture was partitioned. The aqueous layer was further extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution: 0 → 5% ethyl acetate in dichloromethane) to afford 5 (113 mg, 73%) as a white solid (mp 53 -55 °C). Rf 10.19 (dichioromethane); [a]D23 -9.8 ° (c =0.40, CH2C12); 1H NMR (500 MHz, CDCI3, 55 °C) δ 7.38 (m, 10H, Ph-H), 6.00 (s, 1H, ArOCH2OAr), 5.97 (s, 1H, ArOCH2OAr), 5.49 (m (br), 1H, ArCH), 5.19 (m, 3H, Cbz CH2 & CHCO2), 4.72 (m, 3H, Bn CH2 & C02CH2), 4.43 (d, 1H, J = 10.4 Hz, C02CH2), 3.18 (m, 1H, ArCH2), 2.98 (m, 1H, ArCH2), 2.18 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCI3) δ 167.8, 153.1, 149.9, 145.3, 139.3, 136.8, 135.4, 128.5, 128.4, 128.3, 128.1, 127.6, 118.5, 118.1, 114.0, 113.8, 111.5, 101.6, 74.6, 73.4, 67.9, 52.8, 52.1, 45.4, 44.5, 28.1, 27.6, 9.3; IR (neat film) 2920 (w), 1747 (s), 1710 (s), 1455 (s), 1432 (s), 1321 (m), 1299 (s), 1230 (m), 1163 (m), 1096 (s), 1058 (m), 1042 (m) cm-1 ; HRMS (Ef) m/z: calcd for C^H^NO? (M*) 487.1629, found 487.1628.

Example 13 - Aminophenol 6: 6 A mixture of lactone 5 (240 mg, 0.493 mmol, 1 equiv) and 10% palladium on carbon (20 mg) in ethyl acetate (10.0 mL) was stirred under 1 atm , 3H, OCH3), 1.00 (s, 18H, t-butyl), 0.18 (s, 12H, SiCH3), δ (minor isomer) 7.71 (s, 1H, ArCH), 6.65 (s, 2H, ArH), 3.81 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 1.0 (s, 18H, t-butyl), 0.18 (s, 12H, SiCH3); 13C NMR (126 MHz, CDC13) δ 169.9, 165.3, 150.0, 145.8, 144.5, 127.4, 122.5, 116.8, 60.0, 52.8, 25.6, 18.2, -4 7: IR (neat film) 3600-2600 (m, br), 2955 (s), 1741 (s), 1713 (s), 1569 (s), 1493 (s), 1253 (s), 1219 (m), 1096 (s), 864 (s) cm" 1 ; HRMS (FAB-) m/z: Calcd for C24H4o07Si2 (Μ-ΙΓ) 495.2234, found 495.2253.

Example 15 - Benzyl Carbamate 34: To a suspension of 33 (3.35 g, 6.75 mmol, 1 equiv), triethylamine (4.71 mL, 33.8 mmol, 5.0 equiv), and crushed, activated 3 A molecular sieves (- 15 g) in toluene (50 mL) was added diphenylphosphoryl azide (2.90 mL, 13.5 mmol, 2.0 equiv), and the resulting suspension was heated at 70 °C for 2 h. Benzyl alcohol (1.40 mL, 13.5 mmol, 2.0 equiv) then was added to the reaction mixture, and the suspension was stirred at 70 °C for 1 h. The reaction was filtered, washing well with ethyl acetate (100 mL), and the filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in hexane) to afford 34 as a pale yellow oil (3.62 g, 89%). Rf 0.53 (25% ethyl acetate in hexane); 1H NMR (500 MHz, CDC13) δ 7.34 (m, 5H, Cbz ArH), 7.18 (s, 1H, ArCH), 6.77 (s, 2H, ArH), 6.14 (s (br), 1H, NH), 5.13 (s, 2H, Cbz C¾), 3.81 (s (br), 3H, OCH3), 3.75 (s, 3H, OCH3), 1.00 (s, 18H, t-butyl), 0.16 (s, 12H, S1CH3), Z configuration verified by 11.6% NOE of ArH's upon irradiation of NH; ,3C NMR (100 MHz, CDC13) δ 165.8, 149.8, 144.4, 135.8, 132.5, 130.0, 128.5, 128.4, 128.2, 126.1, 123.4, 120.2, 116.4, 67.6, 60.0, 128,993/3 52.5, 25.7, 18.3, -4.7; IR (neat film) 3500 (w, br), 2951 (m), 1723 (s), 1567 (m), 1493 (s), 1424 (m), 1289 (s), 1259 (s), 1122 (s), 1006 (w), 829 (s) cm-1 ; HRMS (FAB"") m/z: Calcd for C31H48 O7 Si2 (MH*) 602.2969, found 602.2993.

Example 16 - Protected Amino Acid 35: Rh[(COD)R,R-DiPAMP]+ BF4" (75 mg) in a mixture of methyl alcohol and dichloromethane (10:1 (v/v), 110 mL) was placed in a high pressure Parr reactor and was purged with hydrogen gas (5 x 50 psi). The reaction mixture was sealed under hydrogen (50 psi) and was stirred at 23 °C for 24 h. The solution was concentrated, and the residue was purified by flash column chromatography (2.5% ethyl acetate in dichloromethane) to yield 35 (6.01 g, quant) as a colorless viscous oil. Rf 0.41 (20% ethyl acetate in hexane); ee: 96% (HPLC ChirlPak AD, 1% isopropyl alcohol in hexanes); [a]D23 +30.5 0 (c=0.40, CH2C12); Ή NMR (400 MHz, CDCI3) δ 7.32 (m, 5H, Cbz ArH), 6.23 (s, 2H, ArH), 5.18 (d, 1H, J = 8.0 Hz, NH), 5.12 (d, 1H, J = 12.3 Hz, Cbz CH2), 5.07 (d, 1H, J = 12.3 Hz, Cbz CH2), 4.59 (m, 1H, ArCH2CH), 3.72 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.95 (d, 2H, J = 5.3 Hz, ArCH2), 0.98 (s, 18H, t-butyl), 0.15 (s, 12H, SiCH3); 13C NMR (100 MHz, CDC13) δ 171.9, 155.6, 149.8, 1.42.1, 136.2, 130.5, 128.5, 128.1, 115.6, 67.0, 59.9, 54.5, 52.2, 37.6, 25.7, 18.3, -4.7; IR (neat film) 3350 (w, br), 2931 (m), 2858 (w), 1728 (s), 1577 (m), 1496 (s), 1434 (s), 1360 (m), 1253 (s), 1230 (s), 1209 (m), 1091 (s), 831 (s) cm'1 ; HRMS (FAB*) m/z: Calcd for C31H5oN07Si2 (MH*) 604.3126, found 604.3103. 128,993/3 Example 17 - Amino Ester 36: A solution of 35 (1.00 g, 1.66 mmol, 1 equiv) and 10% palladium on activated charcoal (50 mg) in ethyl acetate (40 mL) was stirred under 1 atm of hydrogen gas at 23 °C for 2 h. The reaction mixture was gravity filtered, and the filtrate was concentrated to afford 36 (780 mg, quant) as a viscous oil. Rf 0.38 (50% ethyl acetate in hexane); [a]D23 +5.7 0 (c=0.70, CH2C12); 1H NMR (500 MHz, CDC13) δ 6.35 (s, 2H, ArH), 3.71 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.67 (dd, 1H, J = 5.4, 7.9 Hz, CHC02CH3), 2.92 (dd, 1H, J = 5.4, 13.5 Hz, ArCH2), 2.71 (dd, 1H, J = 7.9, 13.5 Hz, ArCH2), 1.00 (s, 9H, t-butyl), 0.19 (s, 6H, Si(CH3)2); 13C NMR (100 MHz, CDC13) δ 175.2, 149.6, 141.7, 132.1, 115.5, 59.8, 55.6, 51.9, 40.5, 25.6, -4.7; FTIR (neat film) 2955 (m), 2930 (m), 2858 (m), 1743 (s), 1577 (s), 1495 (m), 1433 (m), 1356 (m), 1252 (m), 1229 (m), 1087 (s), 858 (s) cm-1 ; HRMS (FAB"1) m/z: Calcd for (MNa+) 492.2578, Found 492.2580.

To a solution of 36 (780 mg, 1.66 mmol, 1 equiv) in pyridine (8 mL) at 0 °C was added dropwise allyl chloroformate (352 mL, 3.32 mmol, 2.0 equiv), and the reaction was stirred at 23 °C for 20 min. The mixture was concentrated 37 128,993/3 The solution was again filtered through a pad of Celite, and the filtrate was concentrated to give the crude aldehyde 8, which was used immediately without further purification in the coupling reaction with 6. Rf 0.33 (25% ethyl acetate in hexanes); lH NMR crude product (400 MHz, CDC13) δ 9.61 (s, 1H, CHO), 6.28 (s, 2H, ArH), 5.90 (m, IH, vinyl H), 5,30 (dd, IH, J*1.2, 17.2 Hz, vinyl H), .21 (m, 2H, vinyl H, NH), 4.58 (m, 2H, allyl H), 4.41 (m, IH, CHCHO), 3.70 (s, 3H, OCH3), 3.01 (dd, IH, J = 6.0, 14.4 Hz, ArCH2), 2.94 (dd, IH, J = 6.8, 14.4 Hz, ArCH2), 0.99 (s, 18H, Si-t-butyl), 0.15 (s, 12H, SiCH3).

Synthesis of the Pentacycle Example 21 - Aminonitrile 37: (1 equiv) (2 equiv) 37 , To a solution of amine 6 (123 mg, 0.467 mmol, 1 equiv) and crude aldehyde 8 (489 mg, 0.935 mmol, 2.0 equiv) in glacial acetic acid (5 mL) was added solid potassium cyanide (608 mg, 9.35 mmol, 20 equiv), and the resulting mixture was stirred at 23 °C for 1 h. The reaction mixture was diluted with ethyl acetate (80 mL) and was washed sequentially with saturated aqueous sodium bicarbonate solution (3 x 60 mL) and saturated aqueous sodium chloride solution (60 mL). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 15% → 20% ethyl acetate in hexane) to afford 37 (159 mg) and its aminonitrile epimer (67 mg) in separate fractions (61% total). 37: Rf 0.19 (25% ethyl acetate in hexane); [a]D23 -36.8 0 (c=1.30, CH2C12); 1HNMR (400 MHz, CDC13) δ (multiple and broadened resonances due to carbamate rotamers at 23 °C) 6.34 (s, 128,993/3 ArH), 6.32 (s, ArH), 6.30 (s, ArH), 5.98-5.80 (m, vinyl H and OCH20), 5.33 (m), 5.28 (m), 5.23 (m), 5.2-4.8 (m (br)), 4.63 (m), 4.57 (m), 4.45 (m (br)), 4.40-4.25 (m) 4.10 (m (br)), 3.93 (m (br)), 3.70 (s, OCH3), 3.61 (s, OCH3), 2.13 (s, ArCH3), 2.08 (s, ArCH3), 1.00 (s, t-butyl), 0.99 (s, t-butyl), 0.19 (s, Si(CH3)2), 0.1 1 is, Si(CH3): 13C NMR (100 MHz, CDC13) δ 171.3, 169.7, 169.2, 156.1, 155.5, 150.1, 150.0, 146.3, 145.1, 142.2, 142.0, 137.9, 132.3, 132.1, 131.3, 130.7, 118.1, 117.9, 117.8, 115.9, 115.5, 115.4, 115.2, 115.0, 110.1, 109.7, 108.9, 107.3, 101.4, 101.3, 73.7, 73.4, 66.0, 60.4, 59.9, 59.8, 57.1, 57.0, 55.2, 55.0, 52.0, 50.7, 47.9, 46.7, 38.2, 35.1, 31.6, 25.7, 22.9, 22.6, 22.0, 21.0, 18.3, 14.1, 8.7, 8.6, -4.7, -4.8; FTIR (neat film) 3300 (m, br), 2955 (s), 2932 (s), 2858 (s), 1727 (s), 1712 (s), 1578 (m), 1495 (m), 1434 (s), 1360 (m), 1255 (s), 1233 (s), 1095 (s), 1043 (m), 1009 (s), 860 (s), 832 (s) cm"1 ; HRMS (FAB4) m/z: Calcd for C4oH58N3010Si2(MH+) 796.3661, Found 796.3636.

Example 22 - Allyl Ether 9: 37 9 128,993/1 To a solution of aminonitrile 37 (986 mg, 1.24 mmol, 1 equiv) in DMF (10 mL) was added sequentially time-dried cesium carbonate (809 mg, 2.78 mmol, 2.0 equiv) and allyl bromide (537 mL, 6.20 mmol, 5.0 equiv), and the mixture was stirred at 23 °C for 1 h. Excess base was neutralized with the addition of acetic acid (4 mL), and the mixture was then partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and dichloromethane (2 x 50 mL). The aqueous layer was further extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (20% ethyl acetate , in hexane) to afford 9 (901 mg, 87%) as a colorless film. Rf 0.41 (25% ethyl acetate in hexane); [afc23 -40.0 0 (c=0.53, CH2C12); lHNMR (500 MHz, CDC¾) δ (multiple and broadened resonances due to carbamate rotamers at 23 °C 6.32 (s, ArH), 6.29 (s, ArH), 6.2-5.7 (m, vinyl H and OC¾0), 5.41 (in, vinyl H), 5.29 (m, vinyl H), 5.31 ( , vinyl H), 5.30-5.10 (m), 4.93 (m (br)), 4.79 (m (br)), 4.70-4.05 (m), 3.91 (m (br)), 3.70 (s, OC¾), 3.60 (s, OCH3), 3.42 (m), 3.19 (m), 3.04-2.89 (m), 2.64 (m), 2.17 (s, ArCH3), 2.10 (s, AxCH3), 1,01 (s, /-butyl), 0.98 (s, i-butyl), 0.18 (s, SitCH3)2), 0.11 (s, Si(CH3)2); UC MR (100 MHz, C CI3) δ 169.3, 168.8, 156.1, 155.4, 150.1, 150.0, 149.9, 149.7, 145.4, 145.3, 142.2, 142.0, 140.4, 140.2, 133.4, 133.3, 132.4, 132.1, 131.3, 130.8, 118.1, 117.9, 117.6, 117.5, 117.1, 116.0, 115.4, 115.2, 115.0, 114.1, 113.8, 109.8, 109.2, 101.7, 101.6, 73.6, 73.5, 73.2, 66.0, 59.9, 59.8, 57.2, 56.9, 55.3, 54.9, 53.4, 52.1, 50.6, 48.2, 46.8, 38.1, 35.13, 25.7, 25.6, 23.5, 22.5, . . 18.3, 9.4, 9.3, -4.7, -4.8; FUR (neat film) 3300 (w, br), 2955 (m), 2932 (s), 2858 (m), 1727 (s), 1577 (m), 1494 (m), 1461 (s), 1434 (m), 1253 (s), 1232 (s), 1095 (s), 1043 (m), 1009 (m), 860 (m), 832 (s) cm"1 ; HRMS (FAB*) m z: Calcd . for C43¾iN3OioSi2 Na (MNa*) 858.3793, found 858.3820. : Example 23 - Triol 10: 39a 128,993/1 To a solution of 9 (390 mg, 0.467 mmol, 1 equiv) in a solution of toluene (50 mL) at -78 °C was added a solution of diisobutylaluminum hydride (1.5 in toluene, 374 mL, 0.560 mmol, 1.2 equiv), and the resulting solution was stirred at -78 °C for 5 h. Excess reducing agent was quenched by the slow sequential addition of methyl alcohol (500 mL), sodium sulfate decahydrate (~ 5 g), and Celite at -78 °C. The suspension was stirred at 23 °C for 1 h before it was filtered , through a pad of Celite. The filtrate was concentrated, and the residue (38) was dissolved in methyl alcohol (4 mL).

To this solution was added potassium fluoride dihydrate (250 mg, 2.66 mmol, 5.7 equiv), and the reaction was stirred at 23 °C for 20 min. The mixture was partitioned between dichoromethane (50 mL) and 80% saturated aqueous sodium chloride solution (80 mL), and the aqueous phase was further extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue (39) was dissolved in dichloromethane (100 mL).

To this solution was added crashed, flamed 3 A molecular sieves (6.20 g) followed by methanesulfonic acid (531 mL, 8.21 mmol, 20 equiv), and the suspension was stirred at 23 °C for 5 h. Excess acid was quenched by the addition of pyridine (1.32 mL, 16.4 mmol, 40 equiv), and the mixture was suction filtered, washing well 10% isopropyl alcohol in dichloromethane (4 x , mL). The product solution was washed with saturated aqueous sodium chloride solution (150 mL), and the aqueous layer was further extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 60% → 100% ethyl acetate in hexane) to afford triol 10 (152 mg, 55%, 3 steps) as a colorless oil. Rf 0.23 (66% ethyl acetate in hexane); [a]D23 -4.4 0 (c=0.48, CH2C12); 1HNMR (500 MHz, CDC13) δ (multiple and broadened resonances due to carbamate rotamers at 23 °C .) 6.32 (s, 1H, ArH), 6.31 (s, 1H, ArH), 6.29 (m, 1H, vinyl H), 5.90 (m, vinyl H, OCH20), 5.60 (s (br), ArOH), 5.50 (s(br), ArOH), 5.42 (m, 1H), 5.39 (m, 1H), 5.32-5.17 (m), 4.91 (m, 1H), 4.83 (m, 1H), 4.62 (m), 4.20 (m), 4.31 (m, 1H), 3.97 (m, 2H), 3.83 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.66-3.20 (m), 2.74 (m, 1H, ArCH2), 2.12 (s, 3H, A1CH3), 0.87 (m, 1H, ArCH2); ,3C NMR (100 MHz, CDC13) δ 171.3, 154.4, 153.9, 148.7, 148.6, 148.4, 146.2, 145.9, 145.5, 144.6, 144.5, 139.0, 133.7, 133.6, 132.6, 132.3, 132.0, 130.8, 130.4, 121.3, 120.6, 120.4, 118.8. 118.0. 117.9. 117.8. 117.5. 117.2. 116.3. 116.1. 115.9. 113.7, 112.5, 113.3. 112.1, 107.7, 107.2, 106.6, 101.2, 74.4, 74.1, 66.8, 66.5, 64.3, 60.9, 60.4, 59.0, 58.9, 58.2, 56.6, 52.9, 51.4, 49.8, 49.4, 48.9, 46.6, 31.0, 30.6, .4, 25.9, 21.0, 14.1, 9.3; FTIR (neat film) 3300 (m, br), 2902 (m), 1686 (s), 1460 (s), 1432 (s), 1372 (m), 1328 (m), 1291 (m), 1264 (w), 1106 (s), 1064 (m), 1027 (m), 954 (m) cm-1 ; HRMS (FAB*) m/z: Calcd for C3iH33N309 Na (MNa+) 614.2114, found 614.2133. solution of 10 (150 mg, 0.253 mmo , 1 equiv) and trietfaylamine (177 42 128,993/4 mL, 1.27 mmol, 5.0 equiv) in dichloromethane (15mL) was added sequentially N-phenyltriflimide (formula; CeHj -N-(S02CF3)2) (227 mg, 0.634 mmol, 2,5 equiv) and DMAP (1 mg), and the reaction was stirred at 23 °C for 6.5 h. Excess base was neutralized by the addition of acetic acid (145 mL, 2.53 mmol, 10 equiv) followed by pyridine (306 mL, 3.79 mmol, 15 equiv). The mixture was partitioned between dichloromethane (50 mL) and saturated aqueous sodium chloride solution (80 mL), and the aqueous layer was further extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the .· residue was purified by flash column chromatography (60% ethyl acetate in hexane) to afford 40 ( 132 mg, 72%) as a colorless film. ¾· 0.44 (50% ethyl acetate in hoxane); [a^23 ÷32.3 0 (c=0.60, C¾C12); !HNMR (500 MHz, CDO3) δ (signals broadened due to carbamate rotamers at 23 °C) 6.65 (s, 1H, ArH), 6.10 (m, 1H, vinyl H), 5.92 (m, vinyl H and OCH20), 5.68 (s, ArOH), . .57 (s (br)), 5.40 (m), 5.26 (m, vinyl H), 4.93 (m), 4.87 (m), 4.63 (m), 4.21 . : ;:¾·.'■ '" ■ (m), 3.98 (m), 3.92 (s, 3H, OC¾), 3.7-3.4 (m), 3.30 (m), 2.86 (m), 2.13 (s, '· ' · 3H, AxCH3), 1.81 (m, 1H, ArCH); 13C NMR (126 MHz, CDCI3) δ 154.1, 153.9, ; ; , 148.7, 148.5, 147.2, 146.6, 144.8, 144.7, 141.1, 140.9, 139.1, B8.9, 136.9, 136.7, 134.2, 133.7, 132.2, 132.1, 131.7, 129.4, 127.1, 123.2, 122.3, 121.3, ■ 121.2, 120.1, 119.9, 119.8, 118.2, 17.6, 117.5, 117.2, 116.2, 116.1, 112.8, 112.7, 112.3, 112.2, 112.1, 1012, 74.4, 66.9, 66.7, 65.6, 65.4, 61.9, 59.5, 59.4, 58.5, 56.5, 49.7, 49.2, 48.9, 8.3, 30.9, 30.3, 25.9, 14.1, 9.3; FIT (neat film): 3350 (w, br), 2928 (w), 1694 (s), 1685 (s), 1451 (s), 1422 (s), 1319 (m), . 1257 (s), 1214 (s), 1138 (s), 1102 (s), 1026 (s), 989 (m) cm'1 ; HRMS (FAB*) τπ/ζ: Calcd for CJ2H32F3N3OU SNa (MNa*) 746.1607, found 746.1616. 42a 128,993/1 Example 25 - Silyl Ether 41: 128, To a solution of 41 (90 mg, 0.124 mmol, 1 equiv) and DMAP (152 mg, 1.24 mmol, 10 equiv) in dichloromethane (10 mL) was added r-butyldiphenyl-silylchloride (162 mL, 0.622 mmol, 5.0 equiv), and the solution was stirred at 23 °C for 13 h. The excess base was quenched by the addition of acetic acid (150 mL), and the mixture was partitioned between water (50 mL), and dichloromethane (3 x 30 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 25% → 50% ethyl acetate in hexane) to afford 41 (106 mg, 89%) as a colorless glassy solid. Rf 0.66 (50% ethyl acetate in hexane); [a]D23 +45.2 0 (c=1.00, CH2C12); 1HNMR (500 MHz, CDCI3) δ (multiple and broadened resonances due to carbamate rotamers at 23 °C) 5.70 (m, lH, ArH), 7.56 (m, ArH), 7.45-7.15 (m, ArH), 6.58 (m, 1H, ArH), 6.06 (m, 1H, vinyl H), 5.90 (m, 1H, vinyl H), 5.80 (s, 1H, OCH2 O), 5.13 (m, 2H, ArOH and OCH2O), 5.4-5.1 (m), 4.92 (m), 4.83 (m), 4.61 (m), 4.20 (m), 4.09 (m), 3.92 (s, 3H, OCH3), 3.7-3.2 (m), 2.98 (m, 1H, ArCH), 2.11 (s, 3H, A1CH3), 1.90 (m, 1H, ArCH), 1.01 (s, t-butyl), 1.00 (s, /-butyl); 13C NMR (126 MHz, CDC13) δ 171.2, 154.2, 148.6, 148.5, 147.4, 146.7, 144.6, 144.4, 141.3, 141.2, 139.3, 139.1. 136.6, 136.4, 135.7, 135.3, 134.8, 133.8, 133.0, 132.5, 132.4, 129.8, 129.7. 127.7, 122.2, 122.1, 120.5, 120.4, 119.9, 118.2, 117.6, 117.5, 1 17.3, 117.2, 1 16.9, 116.7, 112.7, 112.4, 112.1, 111.8, 101.0, 74.4, 69.3, 68.8, 66.8, 66.5, 65.3, 61.9, 60.5, 60.4, 60.3, 59.3, 56.6, 49.8, 49.2, 48.9, 48.3, 31.6, .7, 30.0, 26.8, 26.5, 26.2, 26.1, 22.6, 21.0, 19.0, 14.2, 14.1, 9.3, 9.2; FTIR (neat film) 3350 (w, br), 2951 (m), 1694 (s), 1458 (m), 1451 (s), 1425 (s), 1317 (m), 1257 (m), 1214 (s), 1139 (s), 1110 (s), 1038 (m), 989 (m), 824 (m) cm"' ; HRMS (FAB*) m/z Calcd for CASHSOFSNSOU SSiNa (MNa ) 984.2785, found 984.2771. 128,993/3 Example 26 - Methoxymethyl Ether 42: 42 To a solution of 41 (94 mg, 0.0978 mmol, 1 equiv) and diisopropyl-ethylamine (340 mL, 1.96 mmol, 20 equiv) in dichloromethane (6 mL) at 0 °C was added bromo-methylmethyl ether (80 mL, 0.978 mmol, 10 equiv), and the solution was stirred at 23 °C for 20 min. After the reaction was quenched with methyl alcohol (100 mL), the mixture was partitioned between saturated aqueous sodium bicarbonate solution (30 mL), and dichloromethane (2 x 30 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (25% ethyl acetate in hexane) to afford 42 (90 mg, 92%) as a colorless film. Rf 0.66 (50% ethyl acetate in hexane); [a]D23 +57.0 (c=1.0, CH2C12); !HNMR (400 MHz, CDC13) 128,993/1 δ (multiple and broadened resonances due to carbamate rotamers at 23 °C) 7.6-7.1 (m, 10H, ArH), 6.74 (s, IH, ArH), 6.10 (m, IH, vinyl H), 5.93 (m, IH, vinyl H), 5.81 (s, IH, OCH20), 5.65 (s, IH, OCH20), 5.45-5.13 (m, vinyl H, and OCH20), 4.91 (m, IH), 4.69 (m, IH), 4.59 (m, 2H), 4.16 (m, 2H), 4.07 (m, IH), 3.87 (m, 3H, OCH3), 3.73-3.60 (m, 4H, OCH3 and CHOSi), 3.4-3.2 (m, 3H, CHOSi and ArCH), 2.97 (m, IH, ArCH2), 2.12 (s, 3H, ArCH3), 1.83 (m, IH, ArCH2), 0.97 (m, 9H, t-butyl); I3C NMR (100 MHz, CDC13) δ 154.1, 153.9, 148.5, 147.9, 144.6, 142.6, 142.4, 142.1, 139.3, 139.2, 135.7, 135.3, 134.8, 133.7, 132.9, 132.5, 132.4, 132.3, 129.8, 128.8, 128.7, 127.7, 120.3, 120.1, 118.5, 118.1, 117.5, 117.1, 116.7, 116.6, 116.5, 112.5, 112.4, 112.0, 111.8, 101.1, 99.7, 74.2, 69.2, 68.8, 67.0, 66.7, 61.1, 60.4, 60.2, 59.2, 58.4, 58.1, 56.5, 50.2, 49.3, 49.2, 48.3, 30.7, 30.1, 29.7, 26.8, 26.1, 26.0, 19.0, 9.2; FTIR (neat film) 2959 (m), 1709 (s), 1426 (s), 1315 (m), 1253 (m), 1213 (s), 1140 (s), 1110 (s), 1066 (s), 1015 (s), 987 (s), 921 (s), 825 (m) cm'1 ; MS 45 , (FAB*) m/z: Calcd for C50H54F3 3O12 SSi a (MNa*) 1028, found 1028.

Example 27 - Aminophenol 43: 43 To a solution of 42 (90 mg, 0.0895 mmol, 1 equiv), acetic acid (102 mL, 1.79 mmol, 20 equiv), and dicUoro-bis(triphenylphosphine)palladium (5 mg) in dichloro-methane (4 mL) was added tnbutyltin hydride (120 mL, 0.448 mmol, .0 equiv), and the yellow/brown solution was stirred at 23 °C for l5 min. The mixture was loaded onto a silica gel column, and the product was purified by flash column chromatography (gradient elution: 50% ethyl acetate in hexane → 100% ethyl acetate) to afford 43 (79 mg, quant) as a colorless film. Rf 0.30 (50% ethyl acetate in hexane); [a]D23 +34.0 (c=1.0, CH2C12); 'HJNMR (500 a 128,993/1 MHz, CDCh) δ 7.59 (d, 2H, J = 9.4 Hz, ArH), 7.5-7.2 (m, 8H, ArH), 6.76 (s, 1H, ArH), 5.75 (s, 1H, OCH20), 5.61 (s, 1H, OCH20), 5.39 (d, 1H, J = 5.3 Hz, OCH2O), 5.22 (d, 1H, J = 5.3 Hz, OCH20), 5.14 (s, 1H, ArOH), 4.60 (d, 1H, J = 1.1 Hz, ArCH), 4.49 (d, 1H, J = 2.3 Hz, CHCN), 4.07 (m, 1H, ArCH), 3.85 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.75-3.40 (m (br)), 3.35 (dd, 1H, J = 7.6, 10.2 Hz, CHOSi), 3.28 (dd, 1H, J = ~ 1, 10.2 Hz, CHOSi), 3.13 (m, 2H, ArCH2), 2.94 (d, 1H, J = 15.9 Hz, ArCH2), 2.07 (s, 3H, ArCH3), 1.77 (dd, 1H, J = 11.0, 13.6 Hz, ArCH2), 0.95 (s, 9H, t-butyl); 13C NMR (100 MHz, CDCI3) δ 171.2, 148.4, 145.2, 144.5, 142.0, 141.2, 136.6, 135.6, 135.3, 133.0, 132.9, 132.6, 130.8, 129.7, 127.6, 120.2, 117.9, 117.1, 116.5, 112.4, 111.7, 106.0, 100.6, 99.9, 77.2, 69.2, 61.3, 61.2, 60.4, 59.5, 58.1, 56.8, 49.8, 49.2, 31.0, 26.7, 26.2, 21.0, 19.0, 14.1, 8.7; FTIR (neat film) 3400 ( , br), 2929 (m), 1488 (m), 1460 (m), 1426 (s), 1250 (m), 1213 (s), 1158 (m), 1140 (s), 128,993/3 1105 (s), 1034 (m), 1011 (m), 982 (m), 915 (m), 824 (m) cm-1 ; H MS (FAB+) m/z Calcd for C43H47F3N3O10 SSiNa (MNa*) 882.2704, found 882.2694.

Example 28 - Phenol 44: To a solution of 43 (79 mg, 0.0896 mmol, 1 equiv) and formalin solution (600 mL) in acetonitrile (6 mL) was added solid sodium cyanoborohydride (17 mg, 0.269 mmol, 5.0 equiv), and the solution was stirred at 23 °C for 30 min.

Acetic acid (102 mL, 1.79 mmol, 20 equiv) was added and the reaction was stirred at 23 °C for a further 1.5 h. The rnixture was partitioned between saturated aqueous sodium bicarbonate solution (40 mL) and dichloromethane (30 mL), and the aqueous layer was further extracted with ethyl acetate (2 x 30 mL).

The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 33% → 50% ethyl acetate in hexane) to afford 44 (76 mg, 95%) as a colorless film.

, RF 0.60 (50% ethyl acetate in hexane); [a]D23 +33.5 (c=1.0, CH2C12); 'HNMR (500 MHz, CDC13) δ 7.59 (m, 2H, ArH), 7.46-7.22 (m, 8H, ArH), 6.74 (s, IH, ArH), 5.74 (d, IH, J = 1.5 Hz, OCH20), 5.60 (d, IH, J = 1.5 Hz, OCH20), .35 (d, IH, J = 5.7 Hz, OC¾0), 5.21 (d, IH, J = 5.7 Hz, OCH20), 5.01 (s, IH, ArOH), 4.89 (m, IH), 4.60 (d, IH, J = 3.0 Hz), 4.25 (m, IH), 4.11 (m, IH), 3.86 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.39-3.30 (m, 3H), 3.09 (dd, IH, J = 2.6, 15.2 Hz, ArCH2), 3.01 (dd, IH, J = 7.3, 18.2 Hz, ArCH2), 2.74 (d, IH, J = 18.2 Hz, ArCH2), 2.30 (s, 3H, NCH3), 2.05 (s, 3H, A1CH3), 1.79 (dd, IH, J = 11.3, 15.2 Hz, ArCH2), 0.97 (s, 9H, t-butyl); 13C NMR (100 MHz, CDC13) 5 150.1, 145.1, 144.4, 141.8, 141.7, 136.7, 135.7, 135.3, 133.0, , 132.6.. 132.2, 129.7, 127.6, 126.8, 120.3, 118.3, 118.0, 117.1, 116.0, 112.5, 111.9, 106.1, 100.7, 99.9, 77.2, 69.3, 61.6, 61.3, 58.9, 58.2, 56.9, 56.8, 55.0, 48.7, 41.6, 26.7, 25.8, 25.6, 19.0, 14.1, 8.7; FTIR (neat film) 3400 (w, br), 2932 (m), 1466 (m), 1426 (s), 1249 (m), 1213 (s), 1156 (s), 1140 (s), 1107 (s), 1063 (m), 1035 (m), 1013 (s), 992 (s), 976 (s), 958 (m), 934 (m) cm-1 ; HRMS (FAB 1 ) m/z: Calcd for CA-^FSNSO^ SSi (MH ) 896.2860, found 896.2872.

Example 29 - Phenol 11: To a solution of 44 (17 mg, 0.0190 mmol, 1 equiv), lithium chloride (16 mg, 0.380 mmol, 20 equiv), and dichlorobis(triphenylphosphine)palladium (1 mg) in DMF (0.5 mL) was added tetramethyl tin (53 mL, 0.380 mmol, 20 equiv), and the brown solution was stirred at 80 °C for 2 h. The reaction mixture was partitioned between water (30 mL) and dichloromethane (2 x 20 mL). The aqueous layer was further extracted with ethyl acetate (2 x 20 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The product was purified by flash column chromatography (gradient elution: 33% → 50% ethyl acetate in hexane) to afford 11 (14 mg, 96) as a colorless film. Rf 47a 128,993/1 0.27 (20% ethyl acetate in benzene); [a]D23 +11.2 (c=0.55, CH2C12); 'HNMR (400 MHz, CDCh) δ 7.56 (m, 2H, ArH), 7.41-7.25 (m, 8H, ArH), 6.67 (s, IH, ArH), 5.72 (d, IH, J = 1.0 Hz, OCH20), 5.58 (d, IH, J = 1.0 Hz, OCH20), .51 (s, IH, AiOH), 5.38 (d, IH, J = 5.7 Hz, OCH20), 5.16 (d, IH, J = 5.7 Hz, OCH20), 4.57 (d, IH, J = 2.9 Hz), 4.21 (m, IH), 4.09 (m, IH), 3.72 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.68 (dd, IH, J = 2.1, 10.4 Hz), 3.38-3.26 (m, 3H), 3.11 (dd, IH, J = 2.5, 15.7 Hz, ArCH2), 3.01 (dd, IH, J = 8.9, 17.9 a 128, To a solution of 11 (40 mg, 0.0525 mmol, 1 equiv) in dichloromethane (6 mL) was added benzeneseleninic anhydride (21 mg, 0.0578 mmol, 1.1 equiv), and the purple solution was stirred at 23 °C for 15 min. The mixture was quenched with saturated aqueous sodium bicarbonate solution (6 mL) before it was partitioned between saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (2 x 20 mL). The aqueous layer was further extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution: 33% → 50% ethyl acetate in hexane) to afford 45 (33 mg, 82%) as a colorless film. Rf 0.27 (50% ethyl acetate in hexane); [a]D23 +148.2 (c=0.50, CH2 C12); 1HNMR (400 MHz, CDC13) δ 7.7-7.3 (m, 10H, ArH), 6.54 (s, 1H, ArH), 5.28 (s, 1H, OCH20), 5.23 (s, 1H, 128,993/3 OCH20), 5.02 (d, 1H, J = 5.7 Hz, OCH20), 4.99 (d, 1H, J = 5.7 Hz, OCH20), 4.46 (d, 1H, J = 2.8 Hz), 4.35 (dd, 1H, J = 2.8, 14.5 Hz), 4.05-3.95 (m, 2H), 3.88 (m, 1H), 3.79 (m, 1H), 3.63 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 2.90 (dd, 1H, J = 8.7, 17.8 Hz, ArCH2), 2.39 (d, 1H, J = 17.8 Hz, ArCH2), 2.23 (s, 3H, NCH3), 2.21 (m, 1H, CH2COH), 2.19 (s, 3H, ArCH3), 2.03 (m, 1H, CH2COH), 1.73 (s, 3H, CH3), 1.10 (s, 9H, t-butyl); 13C NMR (100 MHz, CDC13) δ 200.9, 160.2, 148.6, 148.0, 137.7, 135.8, 135.6, 133.6, 132.9, 130.5, 130.2, 129.8, 129.7, 129.6, 129.5, 127.7, 127.6, 127.5, 125.1, 124.4, 117.2, 113.5, 100.2, 99.1, 77.2, 72.9, 64.3, 60.3, 59.7, 59.6, 58.9, 57.7, 56.8, 56.5, 56.2, 55.3, 55.2, 42.6, 41.6, 41.3, 35.6, 26.9, 25.8, .6, 21.0, 19.4, 19.0, 15.8, 14.2, 7.0; FTER. (neat film) 3500 (w, br), 2929 (s), 1634 (s), 1428 (m), 1377 (m), 1346 (s), 1330 (s), 1232 (m), 1145 (s), 112 (s), 1065 (s), 1054 (s), 1034 (s), 1014 (s), 998 (m), 925 (s), 823 (m) cm 1 ; HRMS (FAB+) m/z: Calcd for C44H5iN308SiNa (MNa*) 800.3340, found 800.3313.

Example 31 - Diol 12: , To a solution of 45 (30 mg, 0.0386 mmol, 1 equiv) in THF (4 mL) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 77 mL, 0.0772 mmol, 2.0 equiv), and the solution was stirred at 23 °C for 10 min. The mixture was partitioned between saturated aqueous sodium chloride solution (30 mL) and ethyl acetate (3 x 20 mL). The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution: 75% → 100% ethyl acetate in hexane) to 50 128,993/3 afford 12 (19 mg, 91%) as a colorless film. Rf 0.25 (75% ethyl acetate in hexane); [a]D23 +156.2 (c=0.11, CH2C12); !H MR (500 MHz, CDC13) δ 6.72 (s, 1H, ArH), 5.86 (s, 2H, OCH20), 5.12 (s, 2H, OCH20), 4.10 (m, 2H), 3.92 (s, 3H, OCH3), 3.88 (m, 1H), 3.80 (m, 1H), 3.62 (m, 1H), 3.52 (s, 3H, OCH3), 3.34 (m, 1H), 3.04 (dd, 1H, J = 7.7, 18.0 Hz, ArCH2), 2.68 (m, 1H), 2.62 (d, 1H, J = 18.0 Hz, ArCH2), 2.32 (s, 3H, NCH3), 2.24 (s, 3H, ArCH3), 2.21 (m, 1H, CH2COH), 2.00 (dd, 1H, J = 8.5, 15.1 Hz, CH2COH), 1.80 (s, 3H, CH3); 13C NMR (100 MHz, CDC13) δ 198.7, 158.9, 148.8, 148.4, 140.4, 131.3, 130.3, 125.4, 123.0, 116.9, 111.1, 104.3, 101.6, 99.4, 77.2, 70.3, 61.7, 60.5, 58.5, 58.0, 57.6, 57.2, 5.2, 41.6, 36.3, 25.6, 15.7, 7.2; FTIR (neat film) 3450 (w, br), 2926 (s), 1645 (s), 1417 (m), 1378 (m), 1345 (s), 1234 (m), 1157 (m), 1133 (m), 1089 (m), 1059 (m), 1038 (m), 995 (m), 970 (m), 954 (m), 924 (m) cm-1 ; HRMS (FAB4) mr. Calcd for (MNa+) 562.2165, found 562.2173.

Final Steps 1 , 28,993/3 DMAP (10 mg, 0.0835 mmol, 5.0 equiv) and 1 -(3-dimethylaminopropyl)-S-ethylcarbodiimide^HCl (16 mg, 0.0835 mmol, 5.0 equiv), and the resulting solution was stirred at 23 °C for 1.5 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (2 x 20 mL), and the aqueous layer was further extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 50 → 60% ethyl acetate in hexanes) to afford 13 (13.7 mg, 91%). Rf 0.15 (50% ethyl acetate in hexanes); [a]D23 +200 (c= 0.2, CH2C12); 1H NMR (400 MHz, CDC13) δ 7.75 (m, 2H, ArH), 7.62 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.30 (m, 2H, ArH), 6.63 (s, IH, ArH), 5.90 (m, IH, vinyl H), 5.74 (s, IH, OCH20), 5.71 (s, IH, OCH20), 5.52 (d, IH, J = 8.3 Hz, NH), 5.32 (d, IH, J = 16.7 Hz, vinyl H), 5.22 (d, IH, J = 10.0 Hz, vinyl H), 5.10 (m, 2H, OC¾0), 4.57 (m, 2H), 4.50 (m, IH), 4.23 (dd, IH, J = 6.2, 11.2 Hz), 4.04 (m, IH), 4.00 (dd, IH, J = 2.5, 13.3 Hz), 3.93 (m, IH), 3.84 (m, 3H, OCH3), 3.49 (m, 3H, OCH3), 3.24 (m, IH), 3.08 (m, 3H), 2.95 (m, 3H), 2.44 (d, IH, J = 18.1 Hz), 2.36 (dd, IH, J = 5.8, 15.0 Hz), 2.25 (s, 3H, NCH3), 2.20 (s, 3H, AxCHj), 1.83 (dd, IH, J = 9.4, 15.0 Hz, C(OH)-CH), 1.78 (s, 3H, CH3), 13C NMR (100 MHz, CD2C12) δ 198.7, 170.6, 158.4, 155.8, 149.0, 148.9, 146.1, 142.8, 141.4, 133.0, 131.5, 130.5, 128.0, 127.4, 125.5, 125.1, 123.4, 120.2, 118.0, 117.6, 108.5, 104.6, 102.1, 99.7, 70.9, 66.7, 66.3, 61.2, 60.4, 57.9, 57.2, 56.5, 56.0, 55.7, 54.2, 47.3, 41.5, 37.3, 35.6, 25.9, .9, 7.5; FTIR (neat film) 3400 (w, br), 2921 (m), 1722 (s), 1650 (s), 1448 (m), 1378 (m), 1346 (s), 1251 (m, 1234 (m), 1208 (m), 1205 (m), 1157 (m), 1133 (m), 1054 (m), 1040 (m), 1033 (m), 995 (m) cm"1 ; HRMS (FAB*) m/z: Calcd for C49H52N40n SNa (MNa÷) 927.3251, found 927.3255. 52 128,993/4 14 , To a solution of triflic anhydride (8 mL, 0.0476 mmol, 16.5 equiv) in dichloromethane (2.6 mL) at -78 °C was added DMSO (18 mL, 0.254 mmol, 88 equiv), and the solution was stirred at -78 °C for 15 min. A solution of 13 (2.6 mg, 0.00287 mmol, 1 equiv) in dichloromethane (2.6 mL) was added dropwise to the reaction mixture, which was then stirred at -40 °C for 45 min. To the yellow/green reaction mixture was added diisopropyl-ethylamine (51 mL, 0.288 mmol, 100 equiv), and the yellow solution was stirred at 0 °C for 45 min before excess Swern reagent was quenched by the addition of t-butyl alcohol (13 mg, 0.176 mmol, 61 equiv) at 0 °C. r-Butyl-tetramethyl guanidine (49 mL, 0.288 mmol, 100 equiv) was added to the solution which was stirred at 23 °C for 1.5 h, during which time the solution turned near-colorless. Acetic anhydride (50 mL, 0.530 mmol, 184 equiv) was added, and after 1 h at 23 °C, the reaction mixture was filtered through a short column of silica gel, eluting with 50% ethyl acetate in hexanes. The filtrate was concentrated, and the residue was purified by flash column chromatography (gradient elution: 25 → 33% ethyl acetate in hexanes) to give 14 (1.7 mg, 79%). Rf 0.40 (50% ethyl acetate in hexanes); [a]D23 -6.0, (c = 0.083, CH2C12); 1H NMR (500 MHz, CDCI3) δ 6.80 (s, 1H, ArH), 6.09 (d, 1H, J = 1.4 Hz, OCH2 O), 6.00 (d, 1H, J = 1.4 Hz, OCH20), 5.93 (m, 1H, vinyl H), 5.32 (dd, 1H, J = 1.4, 17.0 Hz, vinyl H), 5.23 (d, 1H, J = 9.9 Hz, vinyl H), 5.22 (d, 1H, J = 5.2 Hz, OCH20), 5.14 (d, 1H, J = 5.2 Hz, OCH20), 5.03 (d, 1H, J = 13.2 Hz), 4.83 (d, 1H, J = 9.3 Hz), 4.52 (m, 3H), 128,993/3 4.31 (m, 2H), 4.24 (s, IH), 4.16 (m, 2H), 3.74 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 3.45 (m, IH, ArCH), 3.40 (m, IH, ArCH), 2.92 (m, IH, ArCH), 2.29 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3), 2.22 (s, 3H, ArCH3), 2.13 (m, IH, ArCH), 2.03 (s, 3H, AcO); 13C NMR (126 MHz, CD2C12) δ 170.7, 168.9, 166.9, 155.6, 150.2, 148.8, 146.1, 141.5, 140.8, 133.5, 132.2, 130.7, 125.3, 120.8, 118.3, 117.9, 113.9, 102.6, 99.5, 66.1, 61.7, 61.0, 60.6, 60.0, 59.6, 59.4, 57.8, 55.4, 55.0, 54.2, 42.1, 41.4, 33.2, 30.1, 24.1, 20.6, 16.0, 14.4, 9.7; FTIR (neat film) 3450 (w, br), 2930 (m), 1760 (s), 1724 (s), 1515 (m), 1507 (m), 1488 (m), 1456 (m), 1436 (m), 1194 (s), 1089 (m), 1062 (m), 1053 (m), 997 (m), 915 (m) cm"1 ; HRMS (FAB*) m/z: Calcd for C37H42N40nSNa (MNa+) 773.2469, found 773.2466.

Example 34 - Amine 47: Bu3SnH(14 equiv), AcOH (66 equiv) , PdCl2(PPh3)2, CH2C12, 23°C, 15 min, 84% a 128,993/1 To a solution of 14 (5.0 mg, 0.00666 mmol, 1 equiv), PdCl2(PPh3)2 (0.5 mg), and acetic acid (4 mL, 0.0666 mmol, 10 equiv) in dichloromethane (1 mL) was added tributyltin hydride (9 mL, 0.0333 mmol, 5.0 equiv), and the brown solution was stirred at 23 °C for 5 min. The reaction mixture was directly loaded onto a silica gel column, and the product was purified by flash column chromatography (gradient elution: ethyl acetate → 4% isopropyl alcohol in ethyl acetate) to give amine 47 (3.6 mg, 84%). Rf 0.25 (ethyl acetate); [a]D23 +10 (c =0.10, CH2C12); 1H NMR (500 MHz, CDC13) δ 6.73 (s, 1H, ArH), 6.08 (d, 1H, J = 1.0 Hz, OCH20), 5.99 (d, 1H, J = 1.0 Hz, OCH20), 5.21 (d, 1H, J = 3.4 Hz, OCH20), 5.14 (d, 1H, J = 3.4 Hz, OCH20), 5.02 (d, 1H, J = 12.0 54 128,993/3 Hz), 4.51 (m, 1H), 4.34 (d, 1H, J = 4.7 Hz), 4.27 (s, 1H), 4.20 (d, 1H, J = Hz), 4.13 (d, 1H, J = 12.0 Hz), 3.79 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.45 (d, 1H, J = 4.7 Hz), 3.41 (m, 1H), 3.31 (m, IH), 2.92 (m, 2H), 2.29 (s, 3H, NCH3), 2.25 (s, 3H, ArCH3), 2.19 (s, 3H, ArCH3), 2.16 (m, IH), 2.04 (s, 3H, AcO); 13C NMR (100 MHz, CD2C12) 174.7, 149.8, 148.7, 141.4, 140.7, 132.7, 132.4, 132.2, 131.6, 130.8, 128.9, 128.8, 125.4, 125.2, 121.2, 118.4, 114.3, 102.5, 99.5, 61.9, 60.2, 60.1, 59.4, 59.2, 57.7, 55.4, 55.0, 54.6, 42.1, 41.5, 35.1, 30.1, 24.1, 20.6, 19.8, 15.8, 9.7; FTIR (neat film) 3100 (w), 2920 (w), 1760 (m), 1749 (m), 1462 (m), 1454 (m), 1446 (m), 1436 (m), 1423 (m), 1266 (s), 1238 (m), 1197 (m), 1160 (m), 1089 (m) cm*1 ; HRMS (FAB*) m/z: Calcd for C33H38N40<>SNa (MNa*) 689.2257, found 689.2243.

Example 35 - Ketone 15: 47 128, To a solution of amine 47 (2.9 mg, 0.00435 mmol, 1 equiv) in a mixture of DMF in dichloromethane (1 :3 (v/v), 640 mL) was added solid 48 (22 mg, 0.0871 mmol, 20 equiv), and the red solution was stirred at 23 °C for 40 min.

DBU (15 mL, 0.0871 mmol, 20 equiv) was added, and the black suspension was stirred at 23 °C for 15 min before saturated aqueous oxalic acid solution (0.5 mL) was added. The yellow mixture was stirred at 23 °C for 30 min before it was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl ether (30 mL). The organic layer was dried (magnesium sulfate) and concentrated, and was filtered through a short plug of silica gel with 50% ethyl 128,993/3 55 acetate in hexanes to give ketone 15 (2.0 mg, 70%). Rf 0.30 (50% ethyl acetate in hexanes); [a]D23 +102 (c=0.10, CH2C12); 1H NMR (400 MHz, CDC13) δ 6.70 (s, 1H, ArH), 6.12 (d, 1H, J = 1.7 Hz, OCH20), 6.03 (d, 1H, J = 1.7 Hz, OCH20), 5.20 (d, 1H, J = 5.5 Hz, OCH20), 5.13 (d, 1H, J = 5.5 Hz, OC¾0), 5.10 (d, 1H, 3 = 12.0 Hz), 4.68 (m,. 1H), 4.40 (s, 1H), 4.38 (dd, 1H, J = 2.1, 5.1 Hz), 4.22 (dd, 1H, J = 2.1, 10.9 Hz), 4.18 (d, 1H, J = 2.8 Hz), 3.75 (s, 3H, OCH3), 3.58 (m, 1H), 3.57 (s, 3H, OCH3), 3.44 (m, 2H), 2.90 (m, 1H), 2.82 (d, 1H, J = 13.3 Hz), 2.71 (d, 1H, J = 17.3 Hz), 2.32 (s, 3H, NCH3), 2.22 (s, 3H, ArCH3), 2.17 (m, 1H), 2.16 (s, 3H, A1CH3), 2.05 (s, 3H, AcO); 13C NMR (100 MHz, CD2C12) δ 149.7, 149.5, 148.8, 146.8, 132.3, 130.8, 125.7, 124.6, 122.4, 120.6, 118.2, 114.0, 102.8, 99.7, 78.2, 62.1, 61.9, 60.4, 59.5, 59.1, 57.8, 55.3, 55.0, 3.8, 41.6, 37.5, 30.5, 30.1, 24.5, 20.4, 16.0, 9.8; FTIR (neat film) 2923 (s), 1764 (s), 1730 (s), 1463 (m), 1456 (s), 1447 (m), 1436 (tn), 1195 (s), 1160 (m), 1089 (s) cm"1 ; HRMS (FAB*) m/z: Calcd for C33H36N3OioS (MH*) 666.2121, found 666.2124. 55a 128,993/1 Ketone 15 (1.7 mg, 0.00256 mmol, 1 equiv), together with phenethyl-amine 16 (10 mg, 0.0599 mmol, 23 equiv) were dissolved in absolute ethanol (500 mL), and to this solution was added silica gel (10 mg). The suspension was stirred at 23 °C for 10 h before the mixture was diluted with ethyl acetate (5 mL) and filtered. The filtrate was concentrated, and the residue was purified by flash column chromato raphy (5% methanol in dichoromethane) to afford 49 (1.7 mg, 82%). Rf 0.32 (5% methanol in dichoromethane); [a]D23 -10 (c=0.10, CH2C12); 1H NMR (400 MHz, CD2CI2) δ 6.86 (s, IH, ArH), 6.52 (s, IH, ArH),: 6.51 (s, 1Ή, ArH), 6.12 (d, IH, J = 0.9 Hz, OCH20), 6.06 (d, IH, J = 0.9 Hz, OCH2O), 5.26 (d, IH. J = 5.6 Hz, OCH20), 5.22 (d, IH, J = 5.6 Hz, OCH2O), 5.06 (d, IH, J = 11.6 Hz), 4.62 (m, IH), 4.42 (d, IH, J = 5.4 Hz), . 4.36 (s, IH), 4.25 (d, IH, J = 2.7 Hz), 4.19 (dd, IH, J = 2.3, 11.4 Hz), 3.84 . (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.55 (m, IH), 3.48 (m, IH), 3.42 (m, IH), 3.12 (m, IH), 3.00 (m, 2H), 2.85 (m, IH), 2.76 (dd, IH, J = 6.9, 13.7 Hz), 2.62 (m, 2H), 2.45 (m, 2H), 2.34 (s, 3H, NC¾), 2.31 (s, 3H, ArCH3), 2.25 (s, 3H, ArCH3), 2.09 (s, 3H, AcO); l3C NMR (100 MHz, CD2CI2) δ 144.8, 141.8, 131.1," 125.3, 125.1, 118.4, 114.5, 114.3, 110.3, 102.5, 99.5, 61.6, 60.3, 59.7, 59.5, 57.7, 55.6, 55.4, 55.1, 54.7, 43.0, 42.2, 41.6, 40.2, 30.1, 29.4, 24.5, 20.4, 15.9, 9.8; FTIR (neat film) 3400 (s, br), . 2950 (s), 1741 (s), 1512 (s), 1462 (s), 1455 (s), 1442 (s), 1226 (s), 1194 (s), 1088 (s), 1052 (s), 1028 (s) cm*1 ; HRMS (FAB*) mJz: Calcd for C42H46N40uSNa (MNa ) 837.2782, found 837.2797.

Example 37 - Ecteinascidin 770 (50): 128,993/1 Methoxymethyl ether 49 (2.8 mg, 0.0034 mmol, 1 equiv) was dissolved in a mixture of trifluoroacetic acid:THF:water (4:1:1 (v/v), 2.8 mL), and the solution was stirred at 23 °C for 9 h. The reaction mixture was diluted with , toluene (8 mL), and the solution was concentrated at 23 °C. All volatiles were removed in vacuo by azeotropic removal with toluene (2 x 2 mL). The residue was purified by flash column chromatography (5% methanol in dichloromethane) to afford 50 (2.2 mg, 78%). Rf 0.28 (5% methanol in dichloromethane); [a]D23 -35 (c=0.10, CH2C12); 1H NMR (400 MHz, CD2C12) δ 6.59 (s, IH, ArH), 6.46 (s, IH, ArH), 6.46 (s, IH, ArH), 6.06 (s, IH, OCH20), 6.01 (s, IH, OCH20), 5.84 (s, lH), 5.47 (s, IH), 5.02 (d, IH, J=l 1.6 Hz), 4.62 (m, IH), 4.28 (m, 2H), 4.18 (d, IH, J=2.6 Hz), 4.14 (m, IH), 3.79 (s, 3H, OCH3), 3.63 (s, 3H, .

OCH3), 3.46 (m, IH), 3.41 (m, IH), 3.08 (m, IH), 2.92 (m, 2H), 2.79 (m, IH), 2.56 (m, IH), 2.3 (m, 2H), 2.28 (m, 2H), 2.32 (s, 3H, NCH3), 2.26 (s, 3H, A1CH3), 2.19 (s, 3H, ArCH3), 2.03 (s, 3H, AcO); 13C NMR (100 MHz, CD2C12) 57a 128, Ecteinascidin 770 (50) (2.2 mg, 0.00285 mmol, 1 equiv) was dissolved in a mixture of acetonitrile and water (3:2 (v/v), 1.0 mL), and to this solution was added solid silver nitrate (15 mg, 0.088 mmol, 30 equiv). The suspension was stirred at 23 °C for 11 h at which time a mixture of saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution (1:1 (v/v), 128, 2.0 iriL) was added. The mixture was stirred vigorously at 23 °C for 15 min before it was partitioned between a mixture of saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution (1:1 (v/v), 15 mL) and dichloromethane (3 x 10 mL). The combined organic layers were dried (sodium sulfate) and filtered through a pad of Celite. The filtrate was concentrated to give clean 1 (2.0 mg, 95%), identical in all respects to that of an authentic sample. HPLC (Zorbax ODS, C18, 4.6 mm x 25 cm, flow rate: 1.0 mlJmin) RT 11.28 min (co-injection, 25% CH3CN in H20 with 0.2% TFA); [a]D23 -34 (c=0.10, CH2CI2); 1H NMR (500 MHz, CDC12) 6 6.59 (s, 1H, ArH), 6.47 (s, 1H, ArH), 6.46 (s, 1H, ArH), 6.03 (d, 1H, J=l.l Hz, OC¾0), 5.98 (d, 1H, J = 1.1 Hz, OCH20), 5.80 (s, lH), 5.09 (d, 1H, J = .9 Hz), 4.77 (s (br), 1H), 4.43 (d, 1H, J = 2.8 Hz), 4.36 (m, 1H), 4.05 (dd, 1H, J = 2.4, 11.2 Hz), 3.79 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.54 ( FOOTNOTES AND INFORMATION DISCLOSURE The following footnotes and/or reference notes have been referred to above. The inventors accordingly wish to cite the publications which follow as potential prior art to the invention claimed herein. In addition, the publications cited below are hereby incorporated herein by reference. , (1) The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group. See, (a) Rinehart, K. L.; Shield, L. S. in Topics in Pharmaceutical Sciences, eds. Breimer, D. D.; Crommelin, D. J. A.; Midha, K. K. (Amsterdam Medical Press, Noordwijk, The Netherlands), 1989, pp. 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L. H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gade, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R. Holt, T; G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, 0. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc.

Natl. Acad. Sci. USA 1992, 89, 11456. See also, U.S. Pat. Nos. ,089,273; 5,149,804; 5,256,663; and 5,478,932, each incorporated herein by reference. (2) Science 1994, 266, 1324. (3) The current clinical plan calls for the administration of three 0.5 mg doses of 1 per patient; personal communication from Dr. Glynn Faircloth, PharmaMar U.S.A., Cambridge, Mass. (4) (a) Prepared from 3,4-methylenedioxyphenyl methoxymethyl ether by the sequence: (1) lithiation at C-2 (3 equiv of BuLi, 3 equiv of tetramethylethylene diamine in hexane at 0 °C for 4 h) and reaction with CH3I (6 equiv at -78 → 23 °C over 15 min) to afford exclusively the 2-methyl derivative (87%); (2) ortho lithiation (2 equiv of BuLi in THF at -30 °C for 13 h) and subsequent formylation with 4 equiv of DMF (64% yield); (3) cleavage of the MeOCH2 protecting group (0.55 equiv 128,993/3 CH3S03H in CH2C12 at 0 °C) and (4) treatment of the resulting 3-methyl-4,5-methylenedioxy salicylaldehyde with 1.5 equiv of NaH in DMF at 0 °C for 5 min and 2 equiv of benzyl bromide at 23 °C for 40 min (86% overall), (b) Prepared from the monoallyl ester of malonic acid by conversion to the mixed anhydride with BOP chloride (Aldrich) and reaction with 2,2-dimethoxyethanol. (5) This step, which involves complete isomerization to the thermodynamically more stable Z-of-acylaminoacrylic ester, represents a generally useful process for the stereospecific synthesis of such compounds. (6) Koenig, K. E. in Asymmetric Synthesis; Morrison, J. D., Ed., Academic Press, Inc., Orlando, Fla., Vol. 5, 1985, p. 71. (7) The conversion 4 → 5 demonstrates a useful method for control of stereochemistry in the tetrahydroisoquinoline series. (8) (a) This step converts the tertiary hydroxyl group of 13 to the O-dimethylsulfonium derivative. The use of oxalyl chloride-DMSO as reagent is unsatisfactory due to interference by chloride in the subsequent steps of quinone methide formation and addition, (b) This step generates the quinone methide probably by cycloelimination of the Swern type oxosulfonium ylide intermediate. (9) Barton, D. H. R.; Elliott, J. D.; Gero, S. D. J. Chem. Soc. Perkin Trans. 1, 1982, 2085. (10) Obtained from Prof. K. L. Rinehart and PharmaMar, U.S.A. (11) For previous work on the synthesis of the saframycins see: (a) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982, 104, 4957. (b) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am.

Chem. Soc. 1990, 112, 3712. (c) Saito, N.; Yamauchi, R; Nishioka, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54, 5391. (12) Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem., 1978, 43 2923. 128, (13) Kofron, W. G.; Baclawski, L. M. J. Org. Chem., 1976, 41, 1979.

The present invention has been described in detail, including the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of the present disclosure, may make modifications and/or improvements on this invention and still be within the scope and spirit of this invention as set forth in the following claims.

Claims (2)

128,993/5 62 Claims

1. A method for the production of an ecteinascidin compound, comprising cleaving the methoxymethyl group (MOM) from a compound of Formula 49 of the following structure: to form ecteinascidin 770 of the following structure: and optionally replacing in the compound ecteinascidin 770 the CN group with an HO group, by AgN03 in CH3CN-H2O, to give ecteinascidin 743 of the following structure: 128,993/5 63 A method according to claim 1 which comprises the steps: (a) reacting 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate to form an α,β-un saturated malonic ester of Formula 2, as a mixture of B an Z isomers, of the following structure: (b) stereospecifically converting the compound of Formula 2 to a compound of Formula 3 of the following structure: 128,993/5 64 by the steps of selective allyl ester cleavage, Curtius rearrangement, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 into a compound of Formula 4 of the following structure: by catalytic hydrogenation over Knowles' catalyst Rh[(COD)J?,i?-DIPAMP]+BF4-; (d) converting the compound of Formula 4 into a compound of Formula 5 of the following structure: by acetal cleavage, wherein isolation and exposure of the resulting aldehyde to BF3Et20 and 4 A mol sieves yields the bridged lactone compound of Formula 5. 128,993/5 65 (e) converting the bridged lactone compound of Formula 5 to the free amino phenol compound of Formula 6 of the following structure: by hydrogenolysis over 10% Pd-C; (f) reacting 3,5-bis-ieri-butyl-dimethyl-silyloxy-4- methoxybenzaldehyde and methyl hydrogen malonate to form a protected a-amino ester compound of Formula 7 of the following structure: (g) reducing the protected a-amino ester compound of Formula 7 to the chiral aldehyde 8 of the following structure: 128,993/5 66 (h) reacting the compounds of Formulae 6 and 8 to give a coupled phenolic a-amino nitrile, followed by O-allylation to give an allyl ether compound of Formula 9 of the following structure: reacting the compound of Formula 9 with diisobutylaluminum hydride to selectively convert the lactone function in the compound of Formula 9 to a lactol; desilylating the lactol compound; and cyclizing the desilylated compound by an internal Mannich bisannulation to afford a monobridged pentacyclic compound of Formula 10; 128,993/5 67 (i) converting the pentacycle compound of Formula 10 to the compound of Formula 11 of the following structure: by the selective trifluoromethane-sulfonation of the least hindered phenolic hydroxyl followed by (1) selective silylation of the primary hydroxyl; (2) protection of the remaining phenolic group as a methoxymethyl ether; (3) double deallylation ; (4) reductive N-methylation; and (5) replacement of CF3SO3 by CH3; (j) oxidizing the phenol compound of Formula 11 effected position- selective angular hydroxylation to give after desilylation a dihydroxy dienone compound of Formula 12 of the following structure: 128,993/5 68 (k) esterifying the primary hydroxyl function of the compound of Formula 12 with (S)-N-allyloxycarbonyl-S-(9-fluorenylmethyl) cysteine to form a compound of Formula 13 of the following structure: (1) transforming the compound of Formula 13 by (1) first reacting the compound of Formula 13 with an in situ generated Swern reagent; (2) followed by the formation of the exendo quinone methide, (3) destruction of the excess Swern reagent; (4) addition of excess N- ieri-butyl-N',N''-tetramethylguanidine to generate a 10-membered lactone bridge; and (5) addition of excess AC2O to acetylate the resulting phenoxide group, to give a bridged lactone compound of Formula 14 of the following structure: 69 128, 993/6 (m) cleaving the N-allyloxycarbonyl group of the compound of Formula 14 and oxidizing the resulting a-amino lactone to the corresponding a-keto lactone by transamination thereby forming a compound of Formula 15 of the following structure: (n) reacting the compound of Formula 15 with 2-[3-hydroxy-4- methoxy-phenyl]ethylamine to stereospecifically form a spiro tetrahydroisoquinoline compound 49 of the following structure: (o) cleaving the methoxymethyl group from the compound of Formula 49 to form ecteinascidin 770, of the following structure: 70 128, 993/5 and optionally replacing in the compound ecteinascidin 770 of the above structure the CN group with an HO group to give ecteinascidin 743 of the following structure: 128,993/4 71 An ecteinascidin compound of the general Formula 1 -A: wherein A the method of claim 1 or claim

2. An ecteinascidin compound of Formula 1-A wherein A is OH produced by a method according to claim 1 of 2. An ecteinascidin compound of Formula 1-A wherein A is CN produced by a method according to claim 1 or 2. An intermediate for use in the method of claim 2, wherein the intermediate a phenol compound of Formula 11